xtremophiles
are the rule breakers of biology. These organisms live in the harshest
environments on earthboiling water holes in Italy, the ice of Antarctic
seas, and hydrothermal vents at the bottom of the ocean. They not only
survive but also thrive under conditions previously thought to prohibit
all forms of life. In recent years, scientists have begun to mine the
genomes of extremophiles for information that might lead to new technologies,
such as heat-resistant molecules for commercial uses, and to breakthroughs
in medicine and the environmental sciences.

The first extremophile to be sequenced was Methanococcus jannaschii,
an organism straight out of science fiction. The single-celled microbe
lives near hydrothermal vents 2,600 meters below sea level, where temperatures
approach the boiling point of water and the pressure is sufficient to
crush an ordinary submarine. There, M. jannaschii survives on carbon
dioxide, hydrogen and a few mineral salts. It cannot tolerate oxygen and
takes care of its energy needs by producing methane.

The weirdness of this creature intrigued scientists at The Institute
for Genome Research (TIGR) in Rockville, Maryland, who, in the mid-nineties,
decided to sequence M. jannaschii. They saw the project as an opportunity
to explore a new theory about evolution. The genome sequence, which was
published in 1996, has helped scientists draw more accurately the evolutionary
tree and sparked the current fascination with extremophile genomes.

Until the 1970s, biologists placed living things into two broad categories,
or domains, based on the structure of their cells. These were the eukaryotesmainly
plants and animals, whose cells had a nucleusand the prokaryotes,
such as bacteria, whose cells did not. In 1977, a microbiologist at the
University of Illinois at Urbana-Champaign, Carl Woese, challenged the
status quo. He proposed that there are actually three domains of life
rather than two.

The third domain, known today as the archaea, is made up of single-celled
organisms that lack a nucleus. Woese argued that despite a superficial
resemblance to bacteria, archaeons have a distinct evolutionary heritage
and therefore belong in a separate category.

Woese had wanted to sequence an archaeal genome since the early 1980s.
"Having been discovered rather late in the game, the archaea were
not very well understood organisms," he says. "You could use
genome sequencing to give you a jump-start on characterizing the archaea."

TIGR sequenced the M. jannaschii genome in order to provide "a
much more comprehensive view of the relationship between organisms of
these three domains of life," recalls Claire Fraser, a member of
the TIGR sequencing team. Until then, the evidence for the existence of
a new biological domain had been largely based on studies of small numbers
of genes.

Methanococcus jannaschii was first plucked from the edge of a
sea-floor chimney known as a white smoker off the coast of Mexico in 1982.
It was named for Holger Jannasch of the Woods Hole Oceanographic Institute
in Massachusetts, the microbiologist who led the research expedition that
identified the organism.

M. jannaschii was like nothing scientists had ever seen before.

Described as 'raisin-like' in appearance under the microscope, M.
jannaschii has a thin, tail-like flagellum on one end that gives the
cell mobility. It grows in thick mats and shares its habitat near fissures
in the Earth's crust with a few other hardy microbes and colonies of giant
tube worms. Its genome contains about 1.7 million base pairs arranged
in one circular chromosome and two smaller pieces, or extrachromosomal
elements. The organism has 1,738 genes.

Methanococcus jannaschii was only the fourth free-living organism
to be completely sequenced. Researchers at TIGR had previously sequenced
two bacteria, Haemophilus influenzae and Mycobacterium genitalium,
and an international consortium had sequenced a eukaryotic genome, Saccharomyces
cerevisiae, or brewer's yeast. With the genome sequence of M. jannaschii
in hand, scientists could for the first time compare genomes from all
three domains of life.

Methanococcus jannaschii was like nothing scientists had ever
seen beforemore than half its genes were completely new. Only 44
percent of the genes matched DNA sequences of known genes. For instance,
only 11 percent of the genes in H. influenzae and 17 percent of
those in M. genitalium matched a sequence from M. jannaschii.
By comparison the two bacteria were very similar: 83 percent of M.
genitalium genes had a counterpart in H. influenzae.

The sequencing of M. jannaschii was funded by the US Department
of Energy (DOE)'s Microbial Genome Project, which, since 1994, has investigated
microbes that might be useful in environmental cleanup, energy production,
or other aspects of DOE's mission. The agency thought that M. jannaschii's
ability to produce methane might be harnessed in the search for renewable
energy sources.

But according to Daniel Drell of the DOE Office of Biological and Environmental
Research, M. jannaschii requires such extreme conditions for growth
that it is difficult to develop practical applications using the microbe.
"I think the contributions that it will make will tend to be more
fundamental," he says.

For example, Sung-Hou Kim and his colleagues at the Lawrence Berkeley
National Laboratory in California have been studying M. jannaschii's
proteins. They are trying to define the repertoire of protein structural
elements, or folds, and understand how protein structure relates to function.

The fact that M. jannaschii grows best in extreme environments
was an asset in the study. Most of the proteins in M. jannaschii
crystallize better than their counterparts in organisms that grow at lower
temperatures, says Kim. "To function at a hot temperature, their
proteins are much sturdier, and thus they crystallize better."

Kim and his colleagues were able to deduce the function of several M.
jannaschii proteins based on their structures, a strategy that may
prove useful in determining the functions of genes and proteins in other
sequenced organisms. "The protein fold repertoire is much simpler
than the protein sequence repertoire," Kim says. Indeed, new and
more efficient strategies are needed to make sense of the data coming
out of genome projects.

"I think we were all in those early days perhaps a bit naïve
in thinking that once we had the genome sequence we would understand the
organism," says Fraser. "Having the parts list is nowhere near
enough to figure out the biology. But it's absolutely the right place
to start."